EP0010156B1 - 6-Arylpyridazine-3-ones, compositions pharmaceutiques les contenant et procédé pour leur préparation - Google Patents

6-Arylpyridazine-3-ones, compositions pharmaceutiques les contenant et procédé pour leur préparation Download PDF

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Publication number
EP0010156B1
EP0010156B1 EP79103396A EP79103396A EP0010156B1 EP 0010156 B1 EP0010156 B1 EP 0010156B1 EP 79103396 A EP79103396 A EP 79103396A EP 79103396 A EP79103396 A EP 79103396A EP 0010156 B1 EP0010156 B1 EP 0010156B1
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EP
European Patent Office
Prior art keywords
formula
general formula
ones
preparation
biphenylyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired
Application number
EP79103396A
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German (de)
English (en)
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EP0010156A1 (fr
Inventor
Erich Dr. Schacht
Hans-Adolf Dr. Kurmeier
Joachim Dr. Gante
Reinhard Dr. Lissner
Guido Dr. Melzer
Dieter Dr. Orth
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Merck Patent GmbH
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Merck Patent GmbH
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Priority to AT79103396T priority Critical patent/ATE1624T1/de
Publication of EP0010156A1 publication Critical patent/EP0010156A1/fr
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/26—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings condensed with carbocyclic rings or ring systems
    • C07D237/30—Phthalazines
    • C07D237/32—Phthalazines with oxygen atoms directly attached to carbon atoms of the nitrogen-containing ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/04—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having less than three double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D237/14—Oxygen atoms

Definitions

  • the object of the invention was to find new compounds with valuable properties, in particular those which can be used for the production of medicaments. This object was achieved by providing the compounds of the formula 1.
  • the compounds of the formula I have valuable pharmacological properties with good tolerability. In particular, they show anti-arteriosclerotic and lipid-lowering effects. They have a cholesterol-lowering effect (detectable in the serum of rats according to the method of Levine et al., Automation in Analytical Chemistry, Technicon Symposium 1967, Mediad, New York. Pages 25-28) and triglyceride-level lowering (detectable according to the method of Noble and Campbell, Clin. Chem. 16 [1970], pages 166-170). Antithrombotic, especially platelet aggregation-inhibiting properties also occur.
  • the compounds of formula 1 can therefore be used as medicaments in human and veterinary medicine. They can also be used as intermediates for the production of further active pharmaceutical ingredients.
  • the invention relates to the 6-arylpyridazin-3-ones of the formula
  • the compounds of the formula I are otherwise prepared by methods known per se, as described in the literature (for example in the standard works such as Houben-Weyl, Methods of Organic Chemistry, Georg-Thieme-Verlag, Stuttgart). namely under reaction conditions as are known and suitable for the reactions mentioned. Use can also be made of variants which are known per se and are not mentioned here in detail.
  • keto acids of the formula II can be prepared by methods known per se, for example by reacting biphenyls of the formula RH with methyl succinic anhydride by the Friedel-Crafts method in the presence of AICI 3 .
  • esters for. B. the alkyl esters, in which the alkyl group preferably has 1-4 carbon atoms, in particular the methyl and ethyl esters.
  • acid halides of the acids of formula II are used, for. B. the acid chlorides or acid bromides.
  • suitable reactive derivatives of the carboxylic acids of the formula can be formed in situ during the reaction without being isolated. These include, for example, the hydrazones of the formula the hydrazides of the formula and the hydrazones of these hydrazides of the formula
  • the other starting materials can also be formed in situ in such a way that they are not isolated from the reaction mixture, but instead are immediately reacted further to give the compounds of the formula 1.
  • Suitable inert solvents are preferably alcohols such as methanol, ethanol, isopropanol, n-butanol, isoamyl alcohol, glycols and their ethers such as ethylene glycol, diethylene glycol, ethylene glycol monomethyl or monoethyl ether (methyl glycol), furthermore ethers, in particular water-soluble ethers such as tetrahydrofuranethane, dioxane (Diglyme); furthermore water and mixtures of these solvents with one another, in particular mixtures with water, for. B. aqueous ethanol.
  • the reaction temperatures are advantageously between about 20 and about 200 °, preferably between 60 and 80 °, the reaction times between about 1 and 3 hours.
  • the compounds of the formula have an asymmetry center. They can therefore be obtained in their preparation as racemates or, if optically active starting materials are used, also in optically active form. Racemates obtained can, if desired, be mechanically or chemically separated into their optical antipodes by methods known per se.
  • the invention furthermore relates to the use of the compounds of the formula 1 for the production of pharmaceutical preparations, in particular by a non-chemical route. Here, they can be brought into a suitable dosage form together with at least one solid, liquid or semi-liquid carrier or auxiliary and optionally together with one or more further active ingredient (s).
  • the invention further relates to agents, in particular pharmaceutical preparations, containing a compound of the formula I.
  • Suitable carriers are organic or inorganic substances which are suitable for enteral (e.g. oral), parenteral or topical application and do not react with the new compounds, for example water, vegetable oils, benzyl alcohols, polyethylene glycols, glycerol triacetate, gelatin, Carbohydrates such as lactose or starch, magnesium stearate, talc, petroleum jelly.
  • tablets, dragees, capsules, syrups, juices or drops are used, for rectal use suppositories, for parenteral use, solutions, preferably oily or aqueous solutions, furthermore suspensions, emulsions or implants, for topical use, ointments, creams or powders.
  • the packaging materials such as paper notes or paper capsules are also suitable carriers.
  • the new compounds can also be lyophilized and the lyophilizates obtained, for. B. can be used for the preparation of injectables.
  • the specified preparations can be sterilized and / or contain auxiliaries such as lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, colors, flavors and / or flavorings. If desired, they can also contain one or more other active ingredients, e.g. B. one or more vitamins.
  • auxiliaries such as lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, colors, flavors and / or flavorings.
  • auxiliaries such as lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, colors, flavors and / or flavorings.
  • they can also contain one or more other active ingredients, e.g. B. one or more vitamins.
  • the compounds of the formula are particularly suitable for the treatment and / or prophylaxis of clinical pictures with elevated values of the serum lipids and thrombosis tendency, of primary and secondary hyperlipoproteinaemia with and without xanthomatosis, of atherosclerosis (coronary sclerosis, cerebral sclerosis, peripheral vascular sclerosis), of diabetic angiopathy ).
  • the substances according to the invention are generally administered in analogy to known, commercially available lipid-lowering agents (for example clofibrate), preferably in doses between about 10 and 1000 mg, in particular between 50 and 500 mg per dosage unit.
  • the daily dosage is preferably between about 0.2 and 100 mg / kg body weight.
  • the particular dose for each particular patient depends on a variety of factors, for example on the effectiveness of the particular compound used, on the age, body weight, general health, sex, on the diet, on the time and route of administration, on the rate of excretion, of drug combinations and the severity of the disease that the therapy applies to. Oral application is preferred.

Claims (4)

1. 6-Arylpyridazine-3-ones de formule générale I
Figure imgb0016
dans laquelle
R représente un reste 4-biphénylyle non substitué ou substitué en position 4' par F.
2. Procédé de préparation des 6-arylpyridazinones de formule générale I selon la revendication 1
Figure imgb0017
dans laquelle
R représente un reste 4-biphénylyle non substitué ou substitué en position 4' par F, caractérisé en ce que l'on fait réagir un acide carboxylique de formule générale II
Figure imgb0018
dans laquelle
R a Ia signification indiquée en référence à Ia formule I, ou un dérivé réactif d'un tel acide carboxylique,

avec l'hydrazine.
3. Procédé de préparation de compositions pharmaceutiques, caractérisé en ce que l'on met sous une forme de dosage appropriée un composé de formule générale I selon Ia revendication 1 avec au moins un véhicule ou produit auxiliaire solide, liquide ou semiliquide et le cas échéant avec une autre substance active.
4. Composition pharmaceutique caractérisée en ce qu'elle contient un composé de formule générale 1 selon la revendication 1.
EP79103396A 1978-10-19 1979-09-12 6-Arylpyridazine-3-ones, compositions pharmaceutiques les contenant et procédé pour leur préparation Expired EP0010156B1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AT79103396T ATE1624T1 (de) 1978-10-19 1979-09-12 6-arylpyridazin-3-one, diese enthaltende pharmazeutische zubereitungen und verfahren zu ihrer herstellung.

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19782845456 DE2845456A1 (de) 1978-10-19 1978-10-19 6-arylpyridazin-3-one und verfahren zu ihrer herstellung
DE2845456 1978-10-19

Publications (2)

Publication Number Publication Date
EP0010156A1 EP0010156A1 (fr) 1980-04-30
EP0010156B1 true EP0010156B1 (fr) 1982-10-06

Family

ID=6052528

Family Applications (1)

Application Number Title Priority Date Filing Date
EP79103396A Expired EP0010156B1 (fr) 1978-10-19 1979-09-12 6-Arylpyridazine-3-ones, compositions pharmaceutiques les contenant et procédé pour leur préparation

Country Status (12)

Country Link
US (1) US4289774A (fr)
EP (1) EP0010156B1 (fr)
JP (1) JPS5557570A (fr)
AT (1) ATE1624T1 (fr)
AU (1) AU532749B2 (fr)
CA (1) CA1134826A (fr)
DE (2) DE2845456A1 (fr)
ES (1) ES485153A1 (fr)
HU (1) HU180264B (fr)
IL (1) IL58473A (fr)
YU (1) YU252479A (fr)
ZA (1) ZA795561B (fr)

Families Citing this family (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3124699A1 (de) * 1981-06-24 1983-01-13 Basf Ag, 6700 Ludwigshafen Neue 2-aryl-3,4-diaza-bicyclo(4.n.0.)alken-(2)-one-(5),verfahren zu ihrer herstellung und diese verbindungen enthaltende arzneimittel
DE3321012A1 (de) * 1983-06-10 1984-12-13 A. Nattermann & Cie GmbH, 5000 Köln Substituierte 4,5-dihydro-6-(thien-2-yl)-3(2h)-pyridazinone und 6-(thien-2-yl)-3(2h)-pyridazinone sowie verfahren zu ihrer herstellung
US4631279A (en) * 1984-10-15 1986-12-23 Eli Lilly And Company 6-(pyridinylphenyl)dihydropyridazinones as inotropic agents
EP0210530A1 (fr) * 1985-07-27 1987-02-04 MERCK PATENT GmbH 6-Arylalcénylpyridazinones
US4806535A (en) * 1987-07-22 1989-02-21 Rorer Pharmaceutical Corporation Imidazolylphenyl and 1,2,4-triazolylphenyl benzopyridazinone and pyridopyridazinone compounds and their use for increasing cardiatonic contractility
GB8824458D0 (en) * 1988-10-19 1988-11-23 Orion Yhtymae Oy Substituted pyridazinones
DE19514568A1 (de) * 1995-04-20 1996-10-24 Merck Patent Gmbh Arylalkyl-pyridazinone
WO1998031674A1 (fr) * 1997-01-15 1998-07-23 Byk Gulden Lomberg Chemische Fabrik Gmbh Phthalazinones
US7074959B2 (en) * 2002-08-01 2006-07-11 New Mexico Highlands University Methods and systems for remediating hydrazine-contaminated equipment and/or surfaces
WO2013097052A1 (fr) 2011-12-30 2013-07-04 Abbott Laboratories Inhibiteurs de bromodomaine
CN104718201A (zh) 2012-06-12 2015-06-17 艾伯维公司 吡啶酮和哒嗪酮衍生物
PL3442972T3 (pl) 2016-04-15 2020-07-27 Abbvie Inc. Inhibitory bromodomeny

Family Cites Families (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1670683A1 (de) * 1966-03-31 1970-01-02 Bayer Ag Verfahren zur Herstellung neuartiger Arylaether
FR1604863A (fr) * 1967-11-22 1972-04-17
US3822260A (en) * 1970-10-09 1974-07-02 American Cyanamid Co 6-(cyanophenyl)-4,5-dihydro-3(2h)-pyridazinones
US3689652A (en) * 1970-10-09 1972-09-05 William Vincent Curran Method of lowering blood pressure in mammals
GB1383906A (en) * 1971-02-22 1974-02-12 Bdh Pharmaceuticals Ltd Pyridazinones
US4088762A (en) * 1971-02-22 1978-05-09 Bdh Pharmaceuticals Limited 6-(P-PIPERAZINO)-PHENYL-4,5-DIHYDRO-3(2H)pyridazinones
US3812256A (en) * 1971-06-08 1974-05-21 American Cyanamid Co Novel method for lowering blood pressure in mammals
US3840662A (en) * 1971-08-05 1974-10-08 Shimamoto Takio Method of treating atherosclerosis using 4-hydroxymethyl-1-keto-1,2-dihydrophthalazine or acid salts thereof
GB1488330A (en) * 1973-12-19 1977-10-12 Smith Kline French Lab Dihydropyridazinones
JPS6037101B2 (ja) * 1977-03-09 1985-08-24 三共株式会社 フエニルピリダジノン誘導体の製法

Also Published As

Publication number Publication date
IL58473A (en) 1985-07-31
ES485153A1 (es) 1980-05-16
DE2963814D1 (en) 1982-11-11
AU5193379A (en) 1980-04-24
EP0010156A1 (fr) 1980-04-30
CA1134826A (fr) 1982-11-02
JPS5557570A (en) 1980-04-28
US4289774A (en) 1981-09-15
AU532749B2 (en) 1983-10-13
YU252479A (en) 1983-01-21
ATE1624T1 (de) 1982-10-15
HU180264B (en) 1983-02-28
IL58473A0 (en) 1980-01-31
DE2845456A1 (de) 1980-08-14
ZA795561B (en) 1980-09-24

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